This invention relates to pharmaceutically useful compounds, in particular compounds which are useful in the inhibition of cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDEs), such as type 5 cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterase (cGMP PDEs). The compounds therefore have utility in a variety of therapeutic areas, including male erectile dysfunction (MED).
International patent application WO 93/07149 discloses certain pyrazolo[3,4-d]pyrimidinone compounds as antianginal agents. International patent application WO 96/16657 discloses the use of these compounds (amongst others) in the treatment of MED.
According to the invention there is provided compounds of formulae IA and IB: 
wherein
A represents CH or N;
R1 and R2 independently represent H, lower alkyl, Het, alkylHet, aryl or alkylaryl, which latter five groups are all optionally substituted (and/or, in the case of lower alkyl, optionally terminated) by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR5, C(O)R6, C(O)OR7, C(O)NR8R9, NR10aR10b and SO2NR11aR11b;
R3 represents H or lower alkyl, which latter group is optionally substituted and/or optionally terminated by one or more substituents selected from aryl, Het, halo, cyano, nitro, OR5, C(O)R6, C(O)OR7, C(O)NR8R9 and NR10aR10b and SO2NR11aR11b;
R4 represents SO2NR12R13;
R12 and R13, together with the nitrogen to which they are attached, form Het;
Het represents an optionally-substituted four- to twelve-membered heterocyclic group, which group contains at least one nitrogen atom and, optionally, one or more further heteroatoms selected from nitrogen, sulphur and oxygen; and
R5, R6, R7, R8, R9, R10a, R10b, R11a and R11b independently represent, at each occurrence when used herein, H or lower alkyl; or a pharmaceutically, or a veterinarily, acceptable derivative thereof; provided that the compound is not:
6-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; or
3-methyl-6-[5-(morpholinosulphonyl)-2-n-propoxyphenyl]-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;
which compounds are referred to together hereinafter as xe2x80x9cthe compounds of the inventionxe2x80x9d.
The term xe2x80x9carylxe2x80x9d, when used herein, includes six- to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl, which groups are optionally substituted with one or more substituents selected from aryl, lower alkyl, Het, halo, cyano, nitro, OR5, C(O)R6, C(O)OR7, C(O)NR8R9, NR10aR10b, SO2NR11aR11b and N(H)SO2R11a.
The term xe2x80x9cHetxe2x80x9d, when used herein, includes four- to twelve-membered, preferably four- to ten-membered, ring systems, which may be wholly or partly aromatic in character. Each xe2x80x9cHetxe2x80x9d group identified herein is optionally substituted by one or more substituents selected from halo, cyano, nitro, lower alkyl (which alkyl group may itself be optionally substituted or terminated a defined below for R14), OR5, C(O)R6, C(O)OR7, C(O)NR8R9 and NR10aR10b, SO2NR11aR11b and N(H)SO2R11a. The term thus includes groups such as optionally substituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl imidazopyridinyl and piperazinyl, e.g. 4-R14-piperazinyl, wherein R14 represents H or lower alkyl, which alkyl group is optionally substituted or terminated by one or more substituents selected from aryl, Het, halo, cyano, nitro, OR5, C(O)R6, C(O)OR7, C(O)NR8R9, NR10aR10b, SO2NR11aR11b and N(H)SO2R11a.
xe2x80x9cHetxe2x80x9d groups may also be in the form of an N-oxide.
For the avoidance of doubt, the nitrogen atom to which R12 and R13 are attached is the nitrogen atom that must be present in the relevant Het group.
The term xe2x80x9clower alkylxe2x80x9d, when used herein, includes C1-6 alkyl. Alkyl groups which R1, R2, R3, R5, R6, R7, R8, R9, R10a, R10b, R11a, R11b and R14 may represent, and with which R1, R2 and Het may be substituted, may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, be cyclic, acyclic or part cyclic/acyclic, be interrupted by oxygen and/or be substituted by one or more halo atom.
The terms xe2x80x9calkylHetxe2x80x9d and xe2x80x9calkylarylxe2x80x9d include C1-6 alkylHet and C1-6 alkylaryl. The alkyl groups (e.g. the C1-6 alkyl groups) of alkylHet and alkylaryl may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, and/or be interrupted by oxygen. When used in this context, the terms xe2x80x9cHetxe2x80x9d and xe2x80x9carylxe2x80x9d are as defined hereinbefore.
Halo groups with which R1, R2, R3, R14, aryl, Het and above-mentioned alkyl groups may be substituted or terminated include fluoro, chloro, bromo and iodo.
Pharmaceutically, and veterinarily, acceptable derivatives includes salts and solvates. Salts which may be mentioned include: acid addition salts, for example, salts formed with inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acid, with carboxylic acids or with organo-sulphonic acids; base addition salts; metal salts formed with bases, for example, the sodium and potassium salts. Pharmaceutically acceptable derivatives also include C1 to C4 alkyl ammonium salts.
Preferred compounds of the invention include those wherein, when the compound is a compound of formula IA, in which R1 represents C1-6 alkyl, R2 represents H, methyl or ethyl, R3 represents C2-4 alkyl and A represents CH, then R12 and R13, together with the nitrogen to which they are attached, do not form a pyrrolidinyl, piperidinyl, morpholinyl, 1-imidazoyl or a 4-R14-piperazinyl (in which R14 represents H, C1-3 alkyl or hydroxyC2-3alkyl) group, which heterocyclic groups are optionally substituted by one or two C1-4 alkyl groups.
Further preferred compounds of the invention include those wherein, when A represents CH, R2 does not represent lower alkyl or H.
Further preferred compounds of the invention include those wherein, when A represents N, R1 represents lower alkyl and R2 represents lower alkyl, Het, alkylHet, aryl or alkylaryl.
Preferred compounds of the invention include those wherein:
R1 represents linear, branched, cyclic, or acyclic, lower alkyl, Het or alkylHet;
R2 represents linear or branched, cyclic, acyclic, or part-cyclic, lower alkyl (which alkyl group is optionally terminated by OH), alkylHet or alkylaryl (the alkyl group of both of which is optionally interrupted by an O atom), aryl or Het;
R3 represents linear or branched lower alkyl, optionally terminated by OR5, where R5 represents H or methyl;
R12 and R13 together with the nitrogen atom to which they are attached, represent 4-R14-piperazinyl, in which R14 is as hereinbefore defined.
More preferred compounds of the invention include those wherein:
R1 represents linear or cyclic C2-5 alkyl, Het or C1-3 alkylHet, in which both latter cases, Het represents a six-membered aromatic ring containing one or two nitrogen atoms;
R2 represents linear or branched, cyclic, acyclic or part-cyclic C1-4 alkyl (which alkyl group is optionally terminated by OH), C1-3 alkylHet (in which Het represents a six-membered heterocyclic group containing one or two nitrogen atoms), C1-3 alkylaryl (the alkyl group of which is optionally interrupted by an O atom), aryl or Het (in which Het represents a six-membered heterocyclic group containing one or two nitrogen atoms);
R3 represents linear or branched C1-4 alkyl, optionally terminated by OR5, where R5 represents H or methyl;
R12 and R13, together with the nitrogen atom to which they are attached, represent 4-R14-piperazinyl, in which R14 represents lower alkyl, optionally terminated by OH.
Particularly preferred compounds of the invention include those wherein:
R1 represents ethyl, n-propyl or cyclopentyl, xe2x80x94CH2-Het (in which Het represents pyridin-2-yl) or pyrimidin-2-yl;
R2 represents methyl, hydroxymethyl, ethyl, propyl or cyclopropylmethyl, xe2x80x94CH2Het (where Het is pyridin-2-yl, pyrimidin-2-yl, morpholinyl or pyrazin-2-yl), benzyl, xe2x80x94CH2OCH2-phenyl, phenyl or pyrazin-2-yl;
R3 represents linear or branched C2-3 alkyl, optionally terminated by OCH3;
R12 and R13, together with the nitrogen atom to which they are attached, represent 4-R14-piperazinyl, in which R14 represents C1-3 alkyl optionally terminated by OH.
Most preferred compounds of the invention include the compounds of Examples 1 to 25 described hereinafter.
The compounds of the invention may exhibit tautomerism. All tautomeric forms of the compounds of formulae IA and IB, and mixtures thereof, are included within the scope of the invention.
The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques e.g. by fractional crystallisation or chromatography. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional techniques e.g. fractional crystallisation or HPLC. The desired optical isomers may be prepared by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation. Alternatively, the desired optical isomers may be prepared by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base. All stereoisomers are included within the scope of the invention.
Also included within the scope of the invention are radiolabelled derivatives of compounds of formulae IA and IB which are suitable for biological studies.
Preparation
According to a further aspect of the invention there is provided processes for the preparation of compounds of the invention, as illustrated below.
The following processes are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention:
1. Compounds of formulae IA and IB may be prepared by cyclisation of corresponding compounds of formulae IIA and IIB, respectively: 
wherein R1, R2, R3, R4 and A are as defined previously for compounds of formulae IA and IB.
This cyclisation may be accomplished under basic, neutral or acidic conditions using known methods for pyrimidone ring formation. Preferably, the cyclisation is performed under basic conditions using an alkali metal salt of an alcohol or amine, such as sodium ethoxide, potassium tert-butoxide or potassium bis(trimethylsilyl) amide, in the presence of a suitable solvent, for example at reflux temperature (or, if performed in a sealed vessel, at greater than reflux temperature). The skilled person will appreciate that, when an alcohol is selected as solvent, an appropriate alcohol of formula R3OH, or a sterically hindered alcohol, eg 3-methyl pentan-3-ol, may be used if it is intended to mitigate alkoxide exchange at either the 2-position of the pyridin-3-yl, or the phenyl, substituent.
Compounds of formulae IIA and IIB may be prepared by reaction of corresponding compounds of formulae IIIA and IIIB, respectively: 
wherein R1 and R2 are as defined previously for compounds of formulae IIA and IIB, with a compound of formula IV or a carboxylic acid derivative thereof: 
wherein R3, R4 and A are as defined previously for compounds of formula IIA and IIB.
This coupling reaction may be achieved by conventional amide bond forming techniques which are well known to those skilled in the art. For example, an acyl halide (e.g. chloride) derivative of a compound of formula IV may be reacted with a compound of formula IIIA or IIIB in the presence of an excess of a tertiary amine, such as triethylamine or pyridine, optionally in the presence of a suitable catalyst, such as 4-dimethyl aminopyridine, in a suitable solvent such as dichloromethane, at a temperature of about 0xc2x0 C. to room temperature.
A variety of other amino acid coupling methodologies may be used to couple the compound of formula IIIA and IIIB with the compound of formula IV. For example, the acid of formula IV or a suitable salt thereof (eg sodium salt) may be activated with an appropriate activating reagent, e.g. a carbodiimide, such as 1,3-dicyclocarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride optionally in the presence of 1-hydroxybenzotriazole hydrate and/or a catalyst such as 4-dimethylaminopyridine; a halotrisaminophosphonium salt such as bromotris(pyrrolidinyl)phosphonium hexafluorophosphate; or a suitable pyridinium salt such as 2-chloro-1-methyl pyridinium chloride. Either type of coupling reaction may be conducted in a suitable solvent such as dichloromethane or tetrahydrofuran, optionally in the presence of a tertiary amine such as N-methylmorpholine or N-ethyldiisopropylamine (for example when either the compound of formula IIIA or IIIB, or the activating agent is presented in the form of an acid addition salt), at from about 0xc2x0 C. to about room temperature. Preferably, from about 1 to 2 molecular equivalents of the activating reagent and from 1 to 3 molecular equivalents of any tertiary amine present may be employed.
Alternatively, the carboxylic acid function of IV may be activated using an excess of a reagent such as N,Nxe2x80x2-carbonyldiimidazole in an appropriate solvent, eg ethyl acetate, dichloromethane or butan-2-one, at from about room temperature to about 80xc2x0 C., followed by reaction of the intermediate imidazolide with either a compound of the formula IIIA or IIIB at from about 20xc2x0 C. to about 90xc2x0 C.
In a further variation, a compound of formula IA or IB, as defined previously, may be formed in a one-pot procedure by coupling a compound of formula IIIA or IIIB with the acyl chloride derivative of formula IV and by cyclising the resultant intermediate compound of formula IIA or IIB, using the methods as described previously. The one-pot procedure may further involve an in-situ coupling and cyclisation reaction to form a compound of formula IA or IB. Preferably, pyridine may serve as an acid scavenger and as the solvent for the in-situ coupling and cyclisation reaction.
2. Compounds of formulae IA and IB may be prepared by cyclisation of corresponding compounds of formulae VA and VB, respectively: 
wherein R1, R2, R3, R4 and A are as defined previously for compounds of formulae IA and IB.
Preferably, the cyclisation is accomplished via hydrolysis, more preferably in the presence of a suitable base such as potassium hydroxide and a suitable solvent, such as a sterically hindered alcohol, such as 3-methyl-3-pentanol, for example at reflux temperature.
Compounds of formulae VA and VB may be prepared by reaction of corresponding compounds of formulae VIA and VIB, respectively: 
wherein R1 and R2 are as previously defined for compounds of formulae VA and VB, with a compound of formula IV or a carboxylic acid derivative thereof as defined previously, using standard amide bond forming techniques, for example as described hereinbefore in respect of the coupling of a compound of formula IIIA or IIIB with a compound of formula IV.
3. Compounds of formulae IA and IB may be prepared by reaction of corresponding compounds of formulae VIIA and VIIB, respectively: 
wherein Y is halo, preferably chloro, bromo or iodo, R1, R2, R3 and A are as previously defined for compounds of formulae IA and IB, with a compound of formula VIII:
R12R13NHxe2x80x83xe2x80x83VIII
wherein R12 and R13 are as previously defined for compounds of formulae IA and IB.
This reaction is typically performed at 0xc2x0 C. to room temperature, preferably in the presence of an appropriate solvent such as a C1 to C3 alcohol or dichloromethane, optionally using an excess of the compound of formula VIII and, optionally, in the presence of another suitable base, such as triethylamine.
Compounds of formulae VIIA and VIIB in which A is CH may be prepared from corresponding compounds of formulae IXA and IXB, respectively: 
wherein R1, R2 and R3 are as previously defined for compounds of formulae VIIA and VIIB, for example using conventional methods for the introduction of a SO2Y group into an aromatic ring system, for example reaction with a compound of formula SO2Y and/or a compound at formula YSO3H. When Y is chloro, an excess of chlorosulphonic acid, optionally with an excess of thionyl chloride, at from about 0xc2x0 C. to room temperature, may be used in an appropriate organic solvent (e.g. dichloromethane).
Compounds of formulae IXA and IXB in which R1 represents lower alkyl, alkylHet or alkylaryl may be prepared by alkylation of a corresponding compound of formula X: 
wherein R2 and R3 are as previously defined for compounds of formulae IXA and IXB, using methods which are well known to those skilled in the art, for example:
(i) reaction of a compound of formula X with a compound of formula R1aL1, wherein R1a represent lower alkyl, alkylHet or alkylaryl, and L1 is a suitable leaving group, using conventional techniques which are well known to those skilled in the art. Preferably, the leaving group is halo (preferably chloro, bromo or iodo) and the alkylation is performed in the presence of an appropriate base, optionally in the presence of sodium iodide or potassium iodide, at from about xe2x88x9270xc2x0 C. to about 100xc2x0 C. Preferably the alkylation is conducted at from about room temperature to about 80xc2x0 C.
Suitable base-solvent combinations may be selected from:
(a) sodium, potassium or cesium carbonate, sodium or potassium bicarbonate, or a tertiary amine such as triethylamine or pyridine, together with a C1 to C4 alkanol, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxan, acetonitrile, pyridine, dimethylformamide or N,N-dimethylacetamide;
(b) sodium or potassium hydroxide, or a sodium or potassium C1 to C4 alkoxide, together with a C1 to C4 alkanol, water or mixtures thereof;
(c) lithium, sodium or potassium hydride, lithium, sodium or potassium bis(trimethylsilyl)amide, lithium diisopropylamide or butyllithium, together with toluene, ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxan; or
(d) under phase transfer catalysis conditions, a tetraalkylammonium halide or hydroxide, together with a mixture of an aqueous solution of sodium or potassium hydroxide and dichloromethane, 1,2-dichloroethane or chloroform;
(ii) reaction of a compound of formula X with a compound of formula R1aOH, wherein R1a is as defined above. Typical reaction conditions involve treating X with the alkanol in the presence of a triarylphosphine and a di(C1 to C4)alkyl azodicarboxylate, in a suitable solvent such as tetrahydrofuran or 1,4-dioxane, at from about xe2x88x9250xc2x0 C. to about room temperature.
Compounds of formulae IXA and IXB, in which R2 represents lower alkyl, alkylHet or alkylaryl, may be alternatively prepared from corresponding compounds of formulae XIA and XIB, respectively: 
wherein R1 and R3 are as previously defined for compounds of formulae IXA and IXB, by reaction with an organometallic compound of formula:
R2aM
wherein M represents for example Li or MgHal, Hal represents halo (e.g. Br) and R2a represents a group which provides the relevant group R2 upon reaction with the xe2x80x94Cxe2x95x90O group which is attached to the pyrazole ring (e.g. when the R2 group to be formed is ethyl, R2a represents methyl and when the R2 group to be formed represents benzyl, R2a represents phenyl), followed by deoxygenation of the resultant secondary alcohol, using methods which are well known to those skilled in the art.
Compounds of formula R2aM are commercially available or are available using well known methods, for example, when M represents Li and R2a represents alkyl, by reacting an alkyl lithium reagent with a compound of the formula R2aZ, wherein Z is a group that undergoes lithium exchange such as halo (eg bromo and iodo) or a tri-alkyl-stannyl group, in a suitable solvent such as tetrahydrofuran at low temperature, preferably below minus 68xc2x0 C. (e.g. xe2x88x9278xc2x0 C.).
Preferably, the compounds of formulae XIA and XIB are reacted with an excess of the reagent R2aM, at low temperatures, preferably below xe2x88x9268xc2x0 C. (e.g. xe2x88x9278xc2x0 C.), in a suitable solvent such as tetrahydrofuran. Preferably, the alcohol functionality of the resultant secondary alcohol is converted to an alkyl group. For example by reaction with thiocarbonyldiimidazole followed by hydride reduction. Typically, the reduction of the derivatised secondary alcohol is effected with a hydrogen atom donor, such as with tri-n-butyltin hydride, in a suitable solvent, such as toluene, at reflux temperature of the reaction.
Compounds of formulae XIA and XIB may be prepared by the oxidation of corresponding compounds of formulae XIIA and XIIB, respectively: 
wherein R1 and R3 are as defined previously for compounds of formulae XIA and XIB, using methods which are well known to those skilled in the art.
Compounds of formulae XIIA and XIIB may be prepared by cyclising corresponding compounds of formulae XIIIA and XIIIB, respectively: 
wherein R1 and R3 are as defined previously for compounds of formulae XIIA and XIIB, and R15 represents an alcohol protecting group, such as benzyl, which is stable to the conditions of the cyclisation reaction, and which may be removed under mild conditions which do not substantially affect the integrity of the resultant compound of formula XIIA or XIIB. The cyclisation reaction may be performed using analogous conditions to those previously described for compounds of formulae IIA and IIB.
Typically, the compounds of formulae XIIIA and XIIIB may be prepared by coupling compounds of the formulae XIVA and XIVB, respectively: 
wherein R1 and R15 are as previously defined for compounds of formulae XIIIA and XIIIB, with a compound of the formula XV or a carboxylic acid derivative thereof: 
wherein R3 is as previously defined for compounds of formulae XIIIA and XIIIB. The coupling reaction may be achieved by conventional amide bond forming techniques which are well known to those skilled in the art, for example, by using techniques which are analogous to those used to couple compounds of formulae IIIA or IIIB with a compound of formula IV.
Compounds of formulae VIIA and VIIB in which A represents N may be prepared from corresponding compounds of formulae XVA and XVB, respectively: 
wherein R1, R2 and R3 are as previously defined for compounds of formulae VIIA and VIIB, for example using methods known to those skilled in the art for converting an amino group to an SO2Y group (in which Y is as previously defined for compounds of formulae VIIA and VIIB). For example, compounds of formulae VIIA and VIIB in which Y is chloro may be prepared by reacting a corresponding compound of formula XVA or XVB with about a two-fold excess of sodium nitrite in a mixture of concentrated hydrochloric acid and glacial acetic acid, at from about xe2x88x9225xc2x0 C. to about 0xc2x0 C., followed by treatment with excess liquid sulphur dioxide and a solution of about a three-fold excess of cupric chloride in aqueous acetic acid, at from about xe2x88x9215xc2x0 C. to about room temperature.
Compounds of formula XVA and XVB may be prepared by cyclisation of a corresponding compound of formula XVC or XVD (as appropriate): 
wherein R1, R2 and R3 are as hereinbefore defined for compounds of formulae XVA and XVB, for example under similar conditions to those described hereinbefore for preparation of compounds of formulae IA and IB.
Compounds of formulae XVA and XVB may alternatively be prepared by reduction of the corresponding nitropyridine compound under conditions which are well known to those skilled in the art. Such nitro compounds may be prepared by cyclisation of appropriate precursors, for example as described above.
4. Compounds of formulae IA and IB, in which R2 represents lower alkyl, alkylHet or alkylaryl, may alternatively be prepared by reaction of corresponding compounds of formulae XVIA and formula XVIB, respectively: 
wherein R1, R3, R4 and A are as previously defined for compounds of formulae IA and IB, with either an organometallic compound of formula R2aM as hereinbefore defined, followed by deoxygenation of the resultant secondary alcohol, using methods which are well known to those skilled in the art, or by reductive amination using a basic compound which provides an R2 group upon reaction with the xe2x80x94Cxe2x95x90O group which is attached to the pyrazole ring (e.g. a group which provides (R2a)xe2x88x92, prior to reaction with the carbonyl, such a morpholinyl), using methods which are well known to those skilled in the art.
Compounds of formulae XVIA and XVIB may be prepared by oxidation of corresponding compounds of formulae IA or IB, in which R2 represents CH2OH using methods which are well known to those skilled in the art.
5. Compounds of formulae IA and IB in which R2 represents CH2OH may be prepared by the deprotection of corresponding compounds of formulae XVIIA and XVIIB, respectively: 
wherein R1, R3, R4 and A are as previously defined for compounds of formulae IA and IB and R15 represents an alcohol protecting group, for example a benzyl group, using methods that are well known to those skilled in the art. (It will be appreciated by those skilled in the art that compounds of formula XVIIA and XVIIB may also be compounds of the invention.)
6. Compounds of formulae IA and IB in which R1 represents lower alkyl, alkylHet or alkylaryl may be prepared by alkylation of corresponding compounds of formulae IA and IB, respectively, in which R1 represents H, for example as described hereinbefore for preparation of compounds of formulae IXA and IXB.
Compounds of formulae IIIA and IIIB, IV, VIA and VIB, VIII, X, XIVA and XIVB, XV, and XVC and XVD, and compounds of formulae R1L1, R1aOH and R2aZ, and derivatives thereof, when not commercially available or not subsequently described, may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily accessible starting materials using appropriate reagents and reaction conditions.
Substituents on the aryl and Het groups in the above-mentioned compounds may be introduced, and interconverted, using techniques which are well known to those skilled in the art.
The skilled person will also appreciate that various standard substituent or functional group interconversions and transformations within certain compounds of formulae IA and IB will provide other compounds of formulae IA and IB. Examples include alkoxide exchange at the 2-position of the 5-phenyl and the pyridin-3-yl substituents, and for compounds in which R1, R2, R3 and R4 represents an alkyl group which is terminated by OH, deprotection of a corresponding ether compound of formula IA or IB (see the Examples below). Moreover, certain compounds of formulae IA and IB, for example those in which R12 and R13, together with the nitrogen to which they are attached, form a 4-R14-piperazinyl group, in which R14 does not represent H, may be prepared directly from the corresponding piperazine analogues in which R14 is hydrogen, using standard procedures (e.g. alkylation).
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the course of carrying out the above processes described above, the functional groups of intermediate compounds may need to be protected by protecting groups.
Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. tertbutyldimethylsilyl, tertbutyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for amino include tertbutyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C1-6 alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by JWF McOmie, Plenum Press (1973), and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, T W Greene and P G M Wutz, Wiley-Interscience (1991).
Persons skilled in the art will also appreciate that, in order to obtain compounds of formula I in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis.
Pharmaceutically acceptable acid addition salts of the compounds of formulae IA and IB which contain a basic centre may be prepared in a conventional manner. For example, a solution of the free base may be treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt may then be isolated either by filtration of by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula IA or IB with the appropriate base. Both types of salt may be formed or interconverted using ion-exchange resin techniques.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula I, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Further, certain compounds of formula I may act as prodrugs of other compounds of formula I.
All protected derivatives, and prodrugs, of compounds of formula I are included within the scope of the invention.
Medical Use
The compounds of the invention are useful because they possess pharmacological activity in animals, especially mammals, including humans. They are therefore indicated as pharmaceuticals, as well as for use as animal medicaments.
According to a further aspect of the invention there is provided the compounds of the invention for use as pharmaceuticals, and for use as animal medicaments.
In particular, compounds of the invention have been found to be potent and selective inhibitors of cGMP PDEs, such as cGMP PDE5, for example as demonstrated in the tests described below, and are thus useful in the treatment of medical conditions in humans, and in animals, in which cGMP PDEs, such as cGMP PDE5, are indicated, and in which inhibition of cGMP PDEs, such as cGMP PDE5, is desirable.
By the term xe2x80x9ctreatmentxe2x80x9d, we include both therapeutic (curative) or prophylactic treatment.
Thus, according to a further aspect of the invention there is provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a medical condition in which a cGMP PDE (e.g. cGMP PDE5) is indicated. There is further provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a medical condition in which inhibition of a cGMP PDE (e.g. cGMP PDE5) is desirable.
The compounds of the invention are thus expected to be useful for the curative or prophylactic treatment of male erectile dysfunction (MED), female sexual dysfunction (FSD), premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable and unstable variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency (e.g. post transluminal coronary angioplasty (post-PTCA)), chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma and diseases characterised by disorders of gut motility (e.g. irritable bowel syndrome (IBS)). Other conditions which may be mentioned include pre-eclampsia, Kawasaki""s syndrome, nitrate tolerance, multiple sclerosis, peripheral diabetic neuropathy, stroke, Alzheimer""s disease, acute respiratory failure, psoriasis, skin necrosis, cancer metastasis, baldness, nutcracker oesophagus, anal fissure and hypoxic vasoconstriction. Particularly preferred conditions include MED and FSD.
Thus, the invention provides a method of treating or preventing a medical condition for which a cGMP PDE5 inhibitor is indicated, in an animal (e.g. a mammal, including a human being), which comprises administering a therapeutically effective amount of a compound of the invention to a mammal in need of such treatment.
Pharmaceutical Preparations
The compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses.
The compounds of the invention may also be combined with any other drugs useful in the inhibition of cGMP-PDEs, such as cGMP-PDE5.
In human therapy, the compounds of the invention can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compounds of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed- or controlled-release applications. The compounds of invention may also be administered via intracavernosal injection.
Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
The compounds of the invention can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. They are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of the compounds of the invention will usually be from 10 to 500 mg/kg (in single or divided doses).
Thus, for example, the tablets or capsules of the compound of the invention may contain from 5 mg to 250 mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
The compounds of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A(trademark) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA(trademark)), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d contains from 1 to 50 mg of a compound of the invention for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 1 to 50 mg, which may be administered in a single dose or, more usually, in divided doses throughout the day.
Alternatively, the compounds of the invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. The compounds of the invention may also be transdermally administered, for example, by the use of a skin patch. They may also be administered by the ocular route, particularly for treating diseases of the eye.
For ophthalmic use, the compounds of the invention can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
For application topically to the skin, the compounds of the invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The skilled person will also be appreciated that, in the treatment of certain conditions (including MED and FSD), compounds of the invention may be taken as a single dose on an xe2x80x9cas requiredxe2x80x9d basis (i.e. as needed or desired).
Generally, in humans, oral administration of the compounds of the invention is the preferred route, being the most convenient and, for example in MED, in avoiding the well-known disadvantages associated with intracavernosal (i.c.) administration.
A preferred oral dosing regimen in MED for a typical man is from 25 to 250 mg of compound when required.
In circumstances where the recipient suffers from a swallowing disorder or from impairment of drug absorption after oral administration, the drug may be administered parenterally, e.g. sublingually or bucally.
For veterinary use, a compound of the invention is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
Thus, according to a further aspect of the invention there is provided a pharmaceutical formulation including a compound of the invention in admixture with a pharmaceutically or veterinarily acceptable adjuvant, diluent or carrier.
In addition to the fact that compounds of the invention inhibit cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDEs) and in particular, are potent and selective inhibitors of cGMP PDE5, compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, be more easily absorbed than, or they may have other useful pharmacological properties over, compounds known in the prior art.
The biological activities of the compounds of the present invention were determined by the following test methods.
Biological Tests
Phosphodiesterase (PDE) Inhibitory Activity
In vitro PDE inhibitory activities against cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate (cGMP) and cyclic adenosine 3xe2x80x2,5xe2x80x2-monophosphate (cAMP) phosphodiesterases were determined by measurement of their IC50 values (the concentration of compound required for 50% inhibition of enzyme activity).
The required PDE enzymes were isolated from a variety of sources, including human corpus cavernosum, human and rabbit platelets, human cardiac ventricle, human skeletal muscle and bovine retina, essentially by the method of W. J. Thompson and M. M. Appleman (Biochem., 1971, 10, 311). In particular, the cGMP-specific PDE (PDE5) and the cGMP-inhibited cAMP PDE (PDE3) were obtained from human corpus cavernosum tissue, human platelets or rabbit platelets; the cGMP-stimulated PDE (PDE2) was obtained from human corpus cavernosum; the calcium/calmodulin (Ca/CAM)-dependent PDE (PDE1) from human cardiac ventricle; the cAMP-specific PDE (PDE4) from human skeletal muscle; and the photoreceptor PDE (PDE6) from bovine retina.
Assays were performed using a modification of the xe2x80x9cbatchxe2x80x9d method of W. J. Thompson et al. (Biochem., 1979, 18, 5228). Results from these tests show that the compounds of the present invention are potent and selective inhibitors of cGMP-specific PDE5.
Functional Activity
This was assessed in vitro by determining the capacity of a compound of the invention to enhance sodium nitroprusside-induced relaxation of precontracted rabbit corpus cavernosum tissue strips, as described by S. A. Ballard et al. (Brit. J. Pharmacol., 1996, 118 (suppl.), abstract 153P).
In Vivo Activity
Compounds may be screened in anaesthetised dogs to determine their capacity, after i.v. administration, to enhance the pressure rises in the corpora cavernosa of the penis induced by intracavernosal injection of sodium nitroprusside, using a method based on that described by TrigoRocha et al. (Neurourol. and Urodyn., 1994, 13, 71).
Safety Profile
Compounds of the invention may be tested at varying i.v and p.o. doses in animals such as mouse and dog, observing for any untoward effects.